SELF-EMULSIFYING COMPOSITION OF w3 FATTY ACID

ABSTRACT

This invention provides a self-emulsifying composition comprising 50 to 95% by weight in total of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids and their pharmaceutically acceptable salts and esters; and 5 to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10. The composition has no or reduced ethanol content, and exhibits excellent self-emulsifying property, dispersibility in the composition, emulsion stability, and absorption property. The composition is adapted for use as a drug.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/409,315, filed Jan. 18, 2017, which is a continuation of U.S.application Ser. No. 14/745,888, filed Jun. 22, 2015, (now U.S. Pat. No.9,579,281 B2) which is a divisional of U.S. application Ser. No.14/069,718, filed Nov. 1, 2013, (now U.S. Pat. No. 9,089,483 B2), whichis a divisional of U.S. application Ser. No. 13/321,801, filed Nov. 21,2011, (now U.S. Pat. No. 8,618,168 B2), which is the National Phase ofPCT International Application No. PCT/JP2010/058676 filed May 21, 2010,which claims priority on Japanese Patent Application No. 2009-124444filed May 22, 2009. The entire contents of each application are herebyincorporated by reference.

TECHNICAL FIELD

This invention provides a self-emulsifying composition containing atleast one compound selected from the group consisting of ω3polyunsaturated fatty acids and their pharmaceutically acceptable saltsand esters thereof. This invention also provides a drug of suchself-emulsifying composition, its production method, and a method forits use.

BACKGROUND ART

Known ω3 polyunsaturated fatty acids (hereinafter abbreviated as ω3PUFA)include α-linolenic acid, eicosapentaenoic acid (hereinafter abbreviatedas EPA), and docosahexaenoic acid (hereinafter abbreviated as DHA).Since ω3PUFA and pharmaceutically acceptable salts and esters thereofhave various actions such as anti-arteriosclerosis action, plateletaggregation suppressive action, blood lipid lowering action,anti-inflammatory action, carcinostatic action, and central action, theyare blended in various food products, and commercially sold in the formof health food and medical and pharmaceutical products.

Ethyl eicosapentaenoate ester (hereinafter abbreviated as EPA-E) iscommercially sold as an oral therapeutic agent for ameliorating ulcer,pain, and coldness associated with arteriosclerosis obliterans as wellas hyperlipidemia (product name Epadel, Mochida Pharmaceutical Co.,Ltd.). When EPA-E is administered orally under fasting, increase inplasma EPA concentration is smaller than the case of the oralaminimistration after the meal conceivably because absorption of theEPA-E requires secretion of bile acid and food coponents as a carrier.Accordingly, Epadel is instructed to be orally administered three timesa day each time immediately after the meal (see Non-Patent Literature1).

However, dosage method or drug compliance has become a problem for thosepeople not taking meals three times a day with the recent change in thelife style, patients who can only take meals at a reduced amount,patients who can only take a fluid diet (milk, rice broth, starch gruel,egg, soup, juice, or oral nutritional supplement), patients with reducedabsorption ability of the intestinal tract (for example, elderly,patients of intestinal disease, patients after intestinal surgery,terminal cancer patients, and patients taking a lipase inhibitor), orpatients who are unable to take meals such as those after the cerebralinfarction.

Recently, attention is paid to the relation between non-fastinghypertriglyceridemia, namely the condition in which serum triglyceride(hereinafter abbreviated as TG) is at its normal value under fastingwhile abnormally increased serum TG value is observed after taking mealor for a prolonged period after taking the meal and coronary arterydisease (see Non-Patent Literature 2), and one cause which may beassociated with this relation is enhancement of sterol regulatoryelement binding protein 1c (hereinafter abbreviated as SREBP1c).Prevention and improvement of lipotoxicity of pancreas β cell under theload of palmitic acid by continuous oral administration of the EPA-Eunder feeding has been reported, and involvement of the suppression ofthe SREBP1c in the mechanism has also been reported (see Non-PatentLiterature 3). However, there is no report for the effectiveness of oraladministration before the meal (under fasting), and an ω3PUFApreparation which is rapidly absorbed even if administered before themeal to suppresses increase of postprandial serum TG is highly awaited.

An emulsion composition containing an ω3PUFA, its pharmaceuticallyacceptable salt or ester exhibiting good processing and storagestability, which is gradually absorbed by oral administration and whichexhibits prolonged absorption for a prolonged period has been reported(see Patent Literature 1). This composition comprises EPA-E and anemulsifier such as a polyglycerin fatty acid ester having a triglycerincontent in polyglycerin of at least 60% or polyoxyethylene sorbitanfatty acid ester.

However, in the case of an emulsion preparation, content of the ω3PUFA,its pharmaceutically acceptable salt or ester which is the effectivecomponent is at most not more than several dozen percents, and moisturecontent is high. Accordingly, the entire amount of the preparation andthe moisture that should be taken for the intake of a pharmaceuticallyeffective amount is inevitably high, and administration of such amountis difficult for the patients such as dialysis patients whose waterintake is limited, and the high water content means difficulty ofcapsulation in a capsule which is made of a material like gelatin. Thehigh moisture content also results in the increase in the handlingtrouble and cost in the production, distribution, and storage.

A self-emulsifying preparation which does not contain water in thepreparation and which is readily dispersible and self-emulsifying inwater has been reported (see Patent Literature 2 and Non-PatentLiterature 4). This preparation contains ω3PUFA and fenofibrate as itseffective components, ethanol, and a surfactant.

Because of the inclusion of the ethanol in the composition, thiscomposition is believed to suffer from the problems such asvolatilization of the ethanol in the course of capsulation, and inparticular, in the step of drying which invites increase in the risk ofcapsule deformation and bubble entrapment, volatilization of the ethanolin the course of distribution and storage which invites increase in therisk of capsule deformation and cracks, and denaturing and turbidity ofthe capsule content caused by the change in the composition due to thevolatilization of the ethanol. Furthermore, such preparation includingthe ethanol can not be taken or such intake is difficult for the alcohol(ethanol) intolerant patients who suffer from face and systemic blush,increase in the heart and respiratory rates, as well as headache andvomiting by the small amount of alcohol intake due to the lack ofaldehyde dehydrogenase which is an alcohol decomposition enzyme or theinsufficient activity of the dehydrogenase. Such people geneticallylacking the alcohol decomposition enzyme or those having low activitydehydrogenase are found in Mongoloids including Japanese at a high rate,and more specifically, in 40 to 45% of Japanese population, and in sucha case, high ethanol content in the preparation should result in variousdisorders as apparent to those skilled in the art. For example,“Dictionary of Drug Additives (in Japanese)” discloses the maximum dailyethanol dose of 3.26 mg in the case of oral administration (seeNon-Patent Literature 5).

In addition, there has so far been no report of the preparation which isless affected by meals and which can be administered to a patient who isunable to take meals or which can be orally administered to a patientunder fasting such as a patient before going to bed; a preparation whichcan rapidly increase blood ω3PUFA concentration by the administrationunder fasting such as administration before the meal or before going tobed and which can rapidly and effectively realize the intendedpharmacological action, for example, suppression of the increase of thepostprandial serum TG; an ω3PUFA preparation which can be encapsulatedin a gelatin capsule or the like and which can be used at a reducedvolume; or a preparation with no or reduced ethanol content that havesolved the ethanol-related problems as described above.

CITATION LIST Patent Literature

-   Patent Literature 1: JP 2008-178341 A-   Patent Literature 2: JP 2008-516890 A

Non-Patent Literature

-   Non-Patent Literature 1: Epadel S (Drug Interview Form), Mochida    Pharmaceutical Co., Ltd., March, 2007-   Non-Patent Literature 2: “Guideline for Diagnosis and Prevention of    Atherosclerotic Cardiovascular Diseases, 2007 Edition” edited by    Japan Atherosclerosis Society and published by Kyowa Kikaku Ltd.,    Apr. 25, 2007-   Non-Patent Literature 3: Diabetes, vol. 57, no. 9, 2382-2392, 2008-   Non-Patent Literature 4: European Journal of Pharmaceutical    Sciences, vol. 33, 351-360, 2008-   Non-Patent Literature 5: “2007 Dictionary of Drug Additives” edited    by International Pharmaceutical Excipients Council Japan and    published by Yakuji Nippo Ltd., Jul. 25, 2007)

SUMMARY OF INVENTION Technical Problems

An object of the present invention is to provide a self-emulsifyingcomposition which contains at least one compound selected from the groupconsisting of ω3PUFA, its pharmaceutically acceptable salts and estersand an emulsifier having a hydrophilic lipophilic balance (hereinafterabbreviated as HLB) of at least 10, which has at least one of excellentself-emulsifying property, dispersibility in the composition, emulsionstability, and absorption property, which contains no ethanol or has alow ethanol concentration, and which is capable of obviating theproblems caused by the ethanol inclusion. The present invention alsoprovides a drug of such self-emulsifying composition, its productionmethod, and the method of its use.

Solution to Problems

In order to solve the problems as described above, the inventors of thepresent invention reduced ethanol content (15% by weight) of theself-emulsifying composition described in Table 4 of Non-PatentLiterature 4, and thereby found that the composition was cloudy and notfully miscible when the ethanol content was reduced to 10% by weight orless. Next, the ethanol was partly substituted with propylene glycolwhich is a polyhydric alcohol, and the composition also became cloudyand not fully miscible when the ethanol content was reduced to 11% byweight or less, and the problems were not solved.

In conducting further intensive investigation, the inventors found thata composition containing at least one compound selected from the groupconsisting of ω3PUFAs and their pharmaceutically acceptable salts andesters at a total content of 50 to 95% by weight and an emulsifierhaving an HLB of at least 10, for example, an emulsifier which is atleast one member selected from polyoxyethylene hydrogenated castor oil,polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil,polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropyleneglycol, sucrose fatty acid ester, and lecithin at a total content of 5to 50% by weight would be a self-emulsifying composition exhibiting atleast one of excellent self-emulsifying property, dispersibility in thecomposition, emulsion stability, and absorption property, and inparticular, oral absorption property and rate under fasting even if noethanol was added or the ethanol was added at a low concentration. Thepresent invention has been completed on the basis of such finding. Theembodiments of the present invention as described below.

(1) A self-emulsifying composition comprising 50 to 95% by weight intotal of at least one compound selected from the group consisting ofω3PUFA and pharmaceutically acceptable salts and esters thereof; and 5to 50% by weight of an emulsifier having a hydrophilic lipophilicbalance of at least 10; wherein ethanol content is up to 4% by weight inrelation to the total content of the compound and the emulsifier.

(2) A self-emulsifying composition according to the above (1) whereincontent of the ethanol is up to 1% by weight.

(3) A self-emulsifying composition according to the above (1) or (2)wherein the composition does not contain ethanol.

(4) A self-emulsifying composition according to any one of the above (1)to (3) wherein the emulsifier is at least one member selected from thegroup consisting of polyoxyethylene hydrogenated castor oil,polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil,polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropyleneglycol, sucrose fatty acid ester, and lecithin.

(5) A self-emulsifying composition according to any one of the above (1)to (4) wherein the emulsifier is at least one member selected from thegroup consisting of polyoxyethylene hydrogenated castor oil,polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil,and sucrose fatty acid ester.

(6) A self-emulsifying composition according to any one of the above (1)to (5) wherein the polyoxyethylene hydrogenated castor oil is at leastone member selected from the group consisting of polyoxyethylene (20)hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil,polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60)hydrogenated castor oil, and polyoxyethylene (100) hydrogenated castoroil.

(7) A self-emulsifying composition according to any one of the above (1)to (5) wherein the polyoxyethylene sorbitan fatty acid ester is at leastone member selected from the group consisting of polyoxyethylenesorbitan monooleate, polyoxyethylene sorbitan tristearate,polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitanmonopalmitate, and polyoxyethylene sorbitan monolaurate.

(8) A self-emulsifying composition according to any one of the above (1)to (5) wherein the sucrose fatty acid ester is at least one memberselected from the group consisting of sucrose laurate, sucrosemyristate, sucrose palmitate, sucrose stearate, and sucrose oleate.

(9) A self-emulsifying composition according to any one of the above (1)to (8) wherein the composition contains a lecithin.

(10) A self-emulsifying composition according to the above (9) whereinthe lecithin is at least one member selected from the group consistingof soybean lecithin, enzymatically decomposed soybean lecithin,hydrogenated soybean lecithin, and egg yolk lecithin.

(11) A self-emulsifying composition according to any one of the above(1) to (8) wherein the composition contains a polyhydric alcohol.

(12) A self-emulsifying composition according to the above (11) whereinthe polyhydric alcohol is at least one member selected from the groupconsisting of divalent alcohols such as ethylene glycol, propyleneglycol, trimethylene glycol, 1,2-butylene glycol, tetramethylene glycol,1,3-butylene glycol, 2,3-butylene glycol, and pentamethylene glycol;trivalent alcohols such as glycerin, trimethylolpropane, and1,2,6-hexanetriol; and polyhydric alcohol polymers such as diethyleneglycol, dipropylene glycol, triethylene glycol, polyethylene glycol,polypropylene glycol, and polyglycerin.

(13) A self-emulsifying composition according to the above (11) whereinthe polyhydric alcohol is propylene glycol or glycerin.

(14) A self-emulsifying composition according to any one of the above(1) to (13) wherein the composition contains lecithin and a polyhydricalcohol.

(15) A self-emulsifying composition according to any one of the above(1) to (14) wherein the emulsifier is at least one member selected fromthe group consisting of polyoxyethylene hydrogenated castor oil,polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene castoroil, and the polyhydric alcohol is propylene glycol.

(16) A self-emulsifying composition according to any one of the above(1) to (14) wherein the emulsifier is a sucrose fatty acid ester and thepolyhydric alcohol is glycerin.

(17) A self-emulsifying composition according to any one of the above(1) to (16) wherein content of the at least one compound selected fromthe group consisting of ω3PUFA and its pharmaceutically acceptable saltsand esters is in the range of 55 to 90% by weight.

(18) A self-emulsifying composition according to any one of the above(1) to (17) wherein content of the at least one compound selected fromthe group consisting of ω3PUFA and its pharmaceutically acceptable saltsand esters is in the range of 60 to 80% by weight.

(19) A self-emulsifying composition according to any one of the above(1) to (18) wherein content of the at least one compound selected fromthe group consisting of ω3PUFA and its pharmaceutically acceptable saltsand esters is in the range of 65 to 75% by weight.

(20) A self-emulsifying composition according to any one of the above(1) to (19) wherein total content of the emulsifier having an HLB of atleast 10 is 10 to 100 parts by weight in relation to 100 parts by weightof the at least one compound selected from the group consisting of ω3PUFA and pharmaceutically acceptable salts and esters thereof.

(21) A self-emulsifying composition according to any one of the above(1) to (20) wherein total content of the emulsifier having an HLB of atleast 10 is 10 to 80 parts by weight in relation to 100 parts by weightof the at least one compound selected from the group consisting of ω3PUFA and pharmaceutically acceptable salts and esters thereof.

(22) A self-emulsifying composition according to any one of the above(1) to (21) wherein total content of the emulsifier having an HLB of atleast 10 is 10 to 50 parts by weight in relation to 100 parts by weightof the at least one compound selected from the group consisting of ω3PUFA and pharmaceutically acceptable salts and esters thereof.

(23) A self-emulsifying composition according to any one of the above(1) to (22) wherein, when the self-emulsifying composition is orallyadministered to a male beagle which has been fasted for at least 18hours at an amount corresponding to 600 mg of the at least one compoundselected from the group consisting of ω3PUFA and pharmaceuticallyacceptable salts and esters thereof, maximum blood ω3PUFA concentration(corrected by subtracting the blood ω3 concentration before theadministration of the composition) is at least 50 μg/ml, and/or areaunder the blood ω3PUFA concentration vs time curve from theadministration to two hours after the administration is at least 50μg/ml·hr.

(24) A self-emulsifying composition according to any one of the above(1) to (22) wherein, when the self-emulsifying composition is orallyadministered to a male beagle which has been fasted for at least 18hours at an amount corresponding to 600 mg of the at least one compoundselected from the group consisting of ω3PUFA and pharmaceuticallyacceptable salts and esters thereof, maximum blood ω3PUFA concentration(corrected by subtracting the blood ω3 concentration before theadministration of the composition) is at least 60 μg/ml, and/or areaunder the blood ω3PUFA concentration vs time curve from theadministration to two hours after the administration is at least 60μg/ml·hr.

(25) A self-emulsifying composition according to any one of the above(1) to (22) wherein, when the self-emulsifying composition is orallyadministered to a male beagle which has been fasted for at least 18hours at an amount corresponding to 600 mg of the at least one compoundselected from the group consisting of ω3PUFA and pharmaceuticallyacceptable salts and esters thereof, maximum blood ω3PUFA concentration(corrected by subtracting the blood ω3 concentration before theadministration of the composition) is at least 70 μg/ml, and/or areaunder the blood ω3PUFA concentration vs time curve from theadministration to two hours after the administration is at least 70μg/ml·hr.

(26) A self-emulsifying composition according to any one of the above(1) to (22) wherein, when the self-emulsifying composition is orallyadministered to a male cynomolgus monkey which has been fasted for atleast 12 hours at an amount corresponding to 45 mg per kg body weight ofthe at least one compound selected from the group consisting of ω3PUFAand pharmaceutically acceptable salts and esters thereof, maximum bloodω3PUFA concentration (corrected by subtracting the blood ω3concentration before the administration of the composition) is at least50 μg/ml, and/or area under the blood ω3PUFA concentration vs time curvefrom the administration to twelve hours after the administration is atleast 400 μg/ml·hr.

(27) A self-emulsifying composition according to any one of the above(1) to (22) wherein, when the self-emulsifying composition is orallyadministered to a male cynomolgus monkey which has been fasted for atleast 12 hours at an amount corresponding to 45 mg per kg body weight ofthe at least one compound selected from the group consisting of ω3PUFAand pharmaceutically acceptable salts and esters thereof, maximum bloodω3PUFA concentration (corrected by subtracting the blood ω3concentration before the administration of the composition) is at least70 μg/ml, and/or area under the blood ω3PUFA concentration vs time curvefrom the administration to twelve hours after the administration is atleast 500 μg/ml·hr.

(28) A self-emulsifying composition according to any one of the above(1) to (22) wherein, when the self-emulsifying composition is orallyadministered to human at an amount corresponding to 1800 mg of the atleast one compound selected from the group consisting of ω3PUFA andpharmaceutically acceptable salts and esters thereof, maximum bloodω3PUFA concentration (corrected by subtracting the blood ω3concentration before the administration of the composition) is at least50 μg/ml, and/or blood ω3PUFA concentration at 2 hours after theadministration is at least 10 μg/ml.

(29) A self-emulsifying composition according to any one of the above(1) to (28) containing at least one member selected from the groupconsisting of EPA, DHA, their pharmaceutically acceptable salts andesters as its effective component.

(30) A self-emulsifying composition according to any one of the above(1) to (29) containing EPA-E and/or ethyl ester of DHA as its effectivecomponent.

(31) A self-emulsifying composition according to any one of the above(1) to (30) containing EPA-E as its effective component.

(32) A self-emulsifying composition according to any one of the above(1) to (31) further comprising at least one member selected from thegroup consisting of polyenephosphatidylcholine, unsaponifiable soybeanoil (soy sterol), gamma-oryzanol, riboflavin butyrate, dextran sulfatesodium sulfur 18, pantethine, elastase, pravastatin, simvastatin,atorvastatin, fluvastatin, pitavastatin, rosuvastatin, cerivastatin,simfibrate, clofibrate, clinofibrate, bezafibrate, fenofibrate,orlistat, cetilistat, colestyramine, colestimide, ezetimibe, vitamin C,vitamin E, tocopherol nicotinate, N-acetylcysteine, probucol,irbesartan, olmesartan medoxomil, candesartan cilexetil, telmisartan,valsartan, losartan potassium, alacepril, imidapril hydrochloride,enalapril maleate, captopril, quinapril hydrochloride, cilazaprilhydrate, temocapril hydrochloride, delapril hydrochloride, trandolapril,benazepril hydrochloride, perindopril, lisinopril hydrate, azelnidipine,amlodipine besylate, aranidipine, efonidipine hydrochloride,cilnidipine, nicardipine hydrochloride, nifedipine, nimodipine,nitrendipine, nilvadipine, barnidipine hydrochloride, felodipine,benidipine, manidipine, tolazoline, phentolamine, atenolol, metoprolol,acebutolol, propranolol, pindolol, carvedilol, labetalol hydrochloride,clonidine, methyldopa, eplerenone, hydrochlorothiazide, furosemide,acarbose, voglibose, miglitol, gliclazide, glibenclamide, glimepiride,tolbutamide, nateglinide, mitiglinide, metformin hydrochloride, buforminhydrochloride, sitagliptin, vildagliptin, alogliptin, saxagliptin,pioglitazone hydrochloride, rosiglitazone maleate, exenatide,liraglutide cilostazol, ticlopidine hydrochloride, alprostadil,limaprost, beraprost sodium, sarpogrelate hydrochloride, argatroban,naftidrofuryl, isoxsuprine hydrochloride, batroxobin, dihydroergotoxinemesilate, tolazoline hydrochloride, hepronicate, shimotsu-to extract,ursodeoxycholic acid, chenodeoxycholic acid, bile powder, deoxycholicacid, cholic acid, bile extract, bear bile, oriental bezoar,dehydrocholic acid, biotin, cyanocobalamin, pantothenic acid, folicacid, thiamine, vitamin K, tyrosine, pyridoxine, leucine, isoleucine,valine, calcium, iron, zinc, copper, magnesium, soy protein, chitosan,low molecular weight sodium alginate, dietary fiber from psyllium seedcoat, soy peptide with bound phospholipids, phytosterol ester, plantstanol ester, diacylglycerol, globin digest, and tea catechin as itssecond effective component.

(33) A self-emulsifying composition according to any one of the above(1) to (32) wherein the moisture content is up to 10% by weight.

(34) A drug which is a self-emulsifying composition comprising 50 to 95%by weight in total of at least one compound selected from the groupconsisting of ω3PUFA and pharmaceutically acceptable salts and estersthereof; and 5 to 50% by weight of an emulsifier having a hydrophiliclipophilic balance of at least 10; wherein ethanol content is up to 4%by weight in relation to the total content of the compound and theemulsifier.

(35) A drug according to the above (34) wherein content of the ethanolis up to 1% by weight.

(36) A drug according to the above (34) or (35) which does not containethanol.

(37) A drug which is a self-emulsifying composition of any one of theabove (1) to (33).

(38) A drug according any one of the above (34) to (37) wherein the drugis at least one member selected from the group consisting of therapeuticagent for dyslipidemia, therapeutic agent for postprandialhypertriglyceridemia, anti-arteriosclerosis agent, platelet aggregationsuppressant, therapeutic agent for peripheral circulatory insufficiency,therapeutic agent for inflammatory disease, anticancer agent, andtherapeutic agent for central disease.

(39) A method for producing the self-emulsifying composition of any oneof the above (1) to (33) comprising the steps of mixing at least 10parts by weight the emulsifier having an HLB of at least 10 in relationto 100 parts by weight in total of the at least one compound selectedfrom the group consisting of ω3PUFA and pharmaceutically acceptablesalts and esters thereof, and homogenizing the mixture (with the provisothat the homogenization is production of a homogeneous composition ofthe ω3PUFA and the emulsifier by dissolution or dispersion which isaccomplished by a step such as heating or stirring).

(40) A method for administering human under fasting or before sleepingwith at least one compound selected from the group consisting of ω3PUFAand pharmaceutically acceptable salts and esters thereof, comprising thesteps of adding at least 10 parts by weight the emulsifier having an HLBof at least 10 to 100 parts by weight in total of the compound, stirringthe mixture, and administering the mixture to human.

(41) A method for increasing plasma ω3PUFA concentration comprising thesteps of adding at least 10 parts by weight the emulsifier having an HLBof at least 10 to 100 parts by weight in total of at least one compoundselected from the group consisting of ω3PUFA and pharmaceuticallyacceptable salts and esters thereof, stirring the mixture, andadministering the mixture to human under fasting or before sleeping tothereby increase the plasma ω3PUFA concentration.

Advantageous Effects of Invention

By adding and dissolving an emulsifier having an HLB of at least 10 toat least one compound selected from the group consisting of ω3PUFA, itspharmaceutically acceptable salts and esters, the present invention iscapable of providing a self-emulsifying composition which has at leastone of excellent self-emulsifying property, dispersibility in thecomposition, emulsion stability, and absorption property, and inparticular, oral absorption property and rate under fasting, and whichcontains no ethanol or has a low ethanol concentration, and which iscapable of obviating the problems caused by the ethanol inclusion. Thepresent invention also provides a drug of such self-emulsifyingcomposition, its production method, and the method of its use.

Compared to conventional compositions, the self-emulsifying compositionof the present invention which can be rapidly absorbed even in the caseof oral administration under fasting is expected to show preventive,ameliorating, and therapeutic effects of the ω3PUFA for variousdiseases. More specifically, the self-emulsifying composition of thepresent invention shows its effectiveness by the administration of 1 to3 times a day at non-limited timing, namely, without the limitation ofthe administering three times a day immediately after the meal, and thisconvenience for the patients leads to the improved drug compliance, andhence, further improvement in the effectiveness. In addition, theself-emulsifying composition of the present invention can be combinedwith a drug which is administered not by the administration immediatelyafter the meal, and a drug which is a combination with such drug mayalso be produced. Furthermore, the self-emulsifying composition of thepresent invention is expected to show various clinical merits such assuppression of the serum TG increase after the meal by administering thecomposition before the meal and prevention of essential fatty aciddeficiency associated with lipase inhibitor administration byadministration of the composition before going to the bed.

Compared to the conventional emulsion preparation, the self-emulsifyingcomposition of the present invention can be produced, delivered, andstored at reduced cost and with less trouble. In addition, theself-emulsifying composition of the present invention can be preparedwater-free with higher concentration of the effective components, andhence, at reduced preparation volume, and this enables administration ofthe composition to patients with water intake restriction. Furthermore,the self-emulsifying composition of the present invention can beencapsulated in a gelatin capsule or the like, and this is expected toimprove both drug convenience and drug compliance.

Due to the non-inclusion or reduced inclusion of the ethanol in theself-emulsifying composition of the present invention, this compositionhas reduced risk of capsule deformation and bubble entrapment by theethanol volatilization during the capsulation step, and in particular,during the drying step, and also, reduced risk of quality change such ascapsule deformation and crack generation by the ethanol volatilizationduring the distribution and storage process. This composition also hasreduced risk of the denaturing such as clouding and separation of thecapsule content by the ethanol volatilization. Furthermore, side effectsof the ethanol are absent or reduced in alcohol (ethanol) intolerantpatients, and it is expected that the composition can be safelyadministered for a long period.

Of the ω3PUFAs and pharmaceutically acceptable salts and esters thereof,EPA-E is known as a highly safe drug effective component. However, onrare occasion, EPA-E suffers from side effects such as vomiturition(0.21%), nausea (0.23%), and stomach discomfort (0.23%). The presentinvention is expected to enable decrease of the dose and/or frequency ofthe at least one compound selected from the group consisting of ω3PUFAand pharmaceutically acceptable salts and esters thereof, and theamelioration of the side effects leads to improvement in the drugcompliance, and also, continuation of the therapy in the patients whowould have been forced to terminate the administration due to the sideeffects.

In addition, an ameliorating or therapeutic drug for chronic diseasessuch as dyslipidemia basically needs continuous administration for along period, and in the case of such administration, the presentinvention is expected to realize amelioration and treatment by reduceddose and frequency.

In advanced countries such as Japan, the U.S., and Europe, use ofalternative medicine has increased, and examples include use of specialpurpose foods, functional health foods (designated health food andfunctional nutritional food), and health foods (supplements). Theself-emulsifying composition containing at least one compound selectedfrom the group consisting of ω3PUFA and pharmaceutically acceptablesalts and esters thereof and an emulsifier having an HLB of at least 10can be provided as a functional health food for human for those in needof the ω3PUFA, for example, those suffering from or those within therisk of suffering from dyslipidemia, peripheral circulatoryinsufficiency, and metabolic syndrome in order to prevent furtheroccurrence of the cerebrovascular event or progress into ulcer andgangrene of extremities and peripheries to thereby maintain the qualityof life.

DESCRIPTION OF EMBODIMENTS

Next, the present invention is described in detail.

The present invention is a self-emulsifying composition comprising 50 to95% by weight in total of at least one compound selected from the groupconsisting of ω3 PFUA and pharmaceutically acceptable salts and estersthereof; and 5 to 50% by weight of an emulsifier having an HLB of atleast 10. The self-emulsifying composition is free from ethanol or theethanol content is low. The present invention also provides a drug ofsuch self-emulsifying composition, its production method, and the methodof its use.

In the present invention, “ω3PUFA” is a fatty acid having a plurality ofcarbon-carbon double bonds in the molecule, and the first double bond isat 3rd position from the end on the side of the methyl group. Typicalexamples include α-linolenic acid, EPA, DHA, eicosatrienoic acid,stearidonic acid, eicosatetraenoic acid, clupanodonic acid,tetracosapentaenoic acid, and nisinic acid. In the present invention,the term “ω3PUFA” include not only the ω3PUFA but also theirpharmaceutically acceptable salts and esters unless otherwise noted.

The ω3PUFA used in the present invention may be a synthetic,semi-synthetic, natural ω3PUFA, or a natural oil containing such ω3PUFA.Examples of the natural ω3PUFA include an extract from a natural oilcontaining an ω3PUFA, a crudely purified natural oil containing anω3PUFA, and a highly purified natural oil containing an ω3PUFA producedby a method known in the art. Exemplary semi-synthetic ω3PUFAs includeω3PUFAs produced by a microorganism or the like and the ω3PUFAs or thenatural ω3PUFAs which have been subjected to a chemical treatment suchas esterification or ester exchange. In the present invention, any oneof the ω3PUFAs may be used alone or in combination of two or more.

In the present invention, EPA and DHA are the preferable examples of theω3PUFAs, and EPA is more preferable. Examples of the pharmaceuticallyacceptable salts of the ω3PUFA include inorganic salts such as sodiumsalts and potassium salts, organic salts such as benzylamine salts anddiethylamine salts, salts with basic amino acids such as arginine saltsand lysine salts, and exemplary esters include alkyl esters such asethyl ester, and esters such as mono-, di- and TG. Preferable examplesinclude ethyl ester and TG ester, and the more preferred is ethyl ester.More specifically, preferable examples include EPA-E, TG ester of EPA,ethyl DHA ester (hereinafter abbreviated as DHA-E), and TG ester of DHA,and among these, the more preferred are EPA-E and DHA-E, and the mostpreferred is EPA-E.

The ω3PUFA used for the starting material of the self-emulsifyingcomposition of the present invention is not particularly limited for itspurity. The purity is typically such that content of the ω3PUFA in thecomposition of the present invention could be preferably at least 50% byweight, more preferably at least 70% by weight, still more preferably atleast 80% by weight, still more preferably at least 90% by weight, andmost preferably at least 96.5% by weight. The ω3PUFA containing EPA-Eand DHA-E at a high purity, for example, the one with the content of(EPA-E+DHA-E) in relation to the ω3PUFA of at least 50% by weight ispreferable, and the content is more preferably at least 60% by weight,still more preferably at least 90% by weight, and most preferably atleast 98% by weight. In other words, the composition of the presentinvention preferably has a high purity of ω3PUFAs in the total fattyacid, more preferably, a high purity of (EPA+DHA) which are ω3PUFAs, andstill more preferably, a high purity of EPA.

For example, when EPA-E and DHA-E are used, compositional ratio ofEPA-E/DHA-E and content of (EPA-E+DHA-E) in relation to total fatty acidare not particularly limited as long as the purity of EPA in thecomposition of the present invention is in the range as described above.However, the compositional ratio of the EPA-E/DHA-E is preferably atleast 0.8, more preferably at least 1.0, and most preferably at least1.2.

The composition of the present invention may also contain apolyunsaturated fatty acid other than the ω3PUFA such as linoleic acid,y linolenic acid, or dihomo-γ-linolenic acid or the pharmaceuticallyacceptable salt or ester thereof. However, content of arachidonic acidis preferably low, more preferably less than 2% by weight, still morepreferably less than 1% by weight, and most preferably, the compositionis substantially free from the arachidonic acid.

In the self-emulsifying composition of the present invention, content ofthe ω3PUFA is 50 to 95% by weight, preferably 55 to 90% by weight, morepreferably 60 to 80% by weight, and still more preferably 65 to 75% byweight.

Compared to the fish oil or the fish oil concentrate, the ω3PUFA used inthe composition or therapeutic agent of the present invention containsimpurities such as saturated fatty acids and arachidonic acid which areunfavorable for cardiovascular events at a lower content, and thisenables realization of the intended action without causing the problemsof excessive nutrition or vitamin A intake. When the ω3PUFA in the formof ester is used, a sufficiently stable composition can be obtained byadding a commonly used antioxidant since the ester form has higheroxidation stability than the fish oils which are mainly TG form.

The ω3PUFA used may be a soft capsule containing the EPA-E at a highpurity (at least 96.5% by weight) (product name, Epadel; manufactured byMochida Pharmaceutical Co., Ltd.) available in Japan as a therapeuticagent for ASO and hyperlipidemia. The ω3PUFA used may also be a mixtureof EPA-E and DHA-E, for example, Lovaza (Registered Tradename) fromGlaxoSmithKline which is a soft capsule containing about 46.5% by weightof EPA-E and about 37.5% by weight of DHA-E) commercially available inthe U.S. as a therapeutic agent for hypertriglyceridemia.

Purified fish oils may also be used for the ω3PUFA, and use ofmonoglyceride, diglyceride, and TG derivatives and combinations thereofof the ω3PUFA are also preferable embodiments. Various productscontaining the ω3PUFA are commercially available, for example, IncromegaF2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525, and E5015(Croda International PLC, Yorkshire, England), and EPAX6000FA,EPAX5000TG, EPAX4510TG, EPAX2050TG, EPAX7010EE, K85TG, K85EE, and K80EE(Pronova Biopharma, Lysaker, Norway). These products may be purchasedand used for the composition of the present invention.

In the present invention, the “polyoxyethylene hydrogenated castor oil”is a compound prepared by addition polymerization of ethylene oxide tothe hydrogenated castor oil which is castor oil having hydrogen addedthereto. Various compounds with different average degree ofpolymerization of ethylene oxide are commercially available, andexamples include polyoxyethylene (20) hydrogenated castor oil (NIKKOLHCO-20, Nikko Chemicals Co., Ltd.), polyoxyethylene (40) hydrogenatedcastor oil (NIKKOL HCO-40, Nikko Chemicals Co., Ltd.), polyoxyethylene(50) hydrogenated castor oil (NIKKOL HCO-50, Nikko Chemicals Co., Ltd.),polyoxyethylene (60) hydrogenated castor oil (NIKKOL HCO-60, NikkoChemicals Co., Ltd.), and polyoxyethylene (100) hydrogenated castor oil(NIKKOL HCO-100, Nikko Chemicals Co., Ltd.), and the preferred ispolyoxyethylene (60) hydrogenated castor oil. These may be used alone orin combination of two or more. In the present invention, the“polyoxyethylene hydrogenated castor oil” includes all of such compoundsunless otherwise noted.

In the present invention, the “polyoxyethylene sorbitan fatty acidester” is polyoxyethylene ether of a fatty acid ester wherein a part ofthe hydroxy groups of anhydrous sorbitol have been esterified with afatty acid. Various compounds with different esterified fatty acid arecommercially available, and examples include polyoxyethylene (20)sorbitan monolaurate (NIKKOL TL-10, Nikko Chemicals Co., Ltd.),polyoxyethylene (20) sorbitan monopalmitate (NIKKOL TP-10V, NikkoChemicals Co., Ltd.), polyoxyethylene (20) sorbitan monostearate (NIKKOLTS-10V, Nikko Chemicals Co., Ltd.), polyoxyethylene (20) sorbitantristearate (NIKKOL TS-30V, Nikko Chemicals Co., Ltd.), polyoxyethylene(20) sorbitan monoisostearate (NIKKOL TI-10V, Nikko Chemicals Co.,Ltd.), polyoxyethylene (20) sorbitan monooleate (NIKKOL TO-10V, NikkoChemicals Co., Ltd.), and polyoxyethylene (20) sorbitan trioleate(NIKKOL TO-30V, Nikko Chemicals Co., Ltd.), and the preferred arepolyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitanmonopalmitate, polyoxyethylene (20) sorbitan monostearate, andpolyoxyethylene (20) sorbitan monooleate, and the more preferred arepolyoxyethylene (20) sorbitan monooleate. These may be used alone or incombination of two or more. In the present invention, the“polyoxyethylene sorbitan fatty acid ester” includes all of suchcompounds unless otherwise noted.

In the present invention, the “polyoxyethylene castor oil” is a compoundprepared by addition polymerization of ethylene oxide to castor oil.Various compounds having different average ethylene oxide mole numberare commercially available, and examples include NIKKOL CO-3 with anaverage ethylene oxide mole number of 3 (Nikko Chemicals Co., Ltd.),NIKKOL CO-10 with an average ethylene oxide mole number of 10 (NikkoChemicals Co., Ltd.), EMALEX C-20 with an average ethylene oxide molenumber of 20 (Nippon Emulsion Co., Ltd.), EMALEX C-30 with an averageethylene oxide mole number of 30 (Nippon Emulsion Co., Ltd.), EMALEXC-40 with an average ethylene oxide mole number of 40 (Nippon EmulsionCo., Ltd.), and EMALEX C-50 with an average ethylene oxide mole numberof 50 (Nippon Emulsion Co., Ltd.). These may be used alone or incombination of two or more. In the present invention, the“polyoxyethylene castor oil” includes all of such compounds unlessotherwise noted.

In the present invention, the “polyethylene glycol fatty acid ester” isa fatty acid ester of a polyethylene glycol which is a fatty acidpolymerized with ethylene oxide. Various compounds with differentesterified fatty acid are commercially available, and examples includepolyethylene glycol monolaurate (NIKKOL MYL-10, Nikko Chemicals Co.,Ltd.), polyethylene glycol monostearate (NIKKOL MYS-10V, MYS-25V,MYS-40V, MYS-45V, and MYS-55V, Nikko Chemicals Co., Ltd.), polyethyleneglycol monooleate (NIKKOL MYO-6 and MYO-10, Nikko Chemicals Co., Ltd.),polyethylene glycol distearate (NIKKOL CDS-6000P, Nikko Chemicals Co.,Ltd.), and polyethylene glycol diisostearate (NIKKOL CDIS-400, NikkoChemicals Co., Ltd.). These may be used alone or in combination of twoor more. In the present invention, the “polyethylene glycol fatty acidester” includes all of such compounds unless otherwise noted.

In the present invention, the “polyoxyethylene polyoxypropylene glycol”is a compound prepared by addition polymerization of ethylene oxide tothe polypropylene glycol which is a polymerized propylene oxide. Variouscompounds having different average degree of polymerization of thepropylene oxide and the ethylene oxide are commercially available, andexamples include polyoxyethylene (3) polyoxypropylene (17) glycol (AdekaPluronic L-31, ADEKA), polyoxyethylene (20) polyoxypropylene (20) glycol(Adeka Pluronic L-44, ADEKA), polyoxyethylene (42) polyoxypropylene (67)glycol (Adeka Pluronic P-123, ADEKA), polyoxyethylene (54)polyoxypropylene (39) glycol (Newdet PE-85, Sanyo Chemical Industries,Ltd.), polyoxyethylene (105) polyoxypropylene (5) glycol (PEP101, SanyoChemical Industries, Ltd.), polyoxyethylene (120) polyoxypropylene (40)glycol (Adeka Pluronic F-87, ADEKA), polyoxyethylene (160)polyoxypropylene (30) glycol (Adeka Pluronic F-68, ADEKA),polyoxyethylene (196) polyoxypropylene (67) glycol (Lutrol F127, BASFJapan), and polyoxyethylene (200) polyoxypropylene (70) glycol, and thepreferred is polyoxyethylene (105) polyoxypropylene (5) glycol. Thesemay be used alone or in combination of two or more. In the presentinvention, the “polyoxyethylene polyoxypropylene glycol” includes all ofsuch compounds unless otherwise noted.

In the present invention, the “sucrose fatty acid ester” is an ester ofsugar and a fatty acid. Various compounds with different types of theesterified fatty acids and degree of esterification are commerciallyavailable, and examples include Surfhope SE PHARMA J-1216 containing 95%of lauric acid in the fatty acid (Mitsubishi-Kagaku Foods Corporation),Surfhope SE PHARMA J-1416 containing 95% of myristic acid in the fattyacid (Mitsubishi-Kagaku Foods Corporation), Surfhope SE PHARMA J-1615and J-1616 containing 80% of palmitic acid in the fatty acid,(Mitsubishi-Kagaku Foods Corporation), J-1811, J-1815, and J-1816containing 70% of stearic acid in the fatty acid (Mitsubishi-KagakuFoods Corporation), and Surfhope SE PHARMA J-1715 containing 70% ofoleic acid in the fatty acid, which may be used alone or in combinationof two or more. The “sucrose fatty acid ester” used in the presentinvention include all of such compounds.

The emulsifier added to the self-emulsifying composition of the presentinvention may have an HLB of at least 10, preferably at least 11, andmore preferably at least 12.

Total content of the emulsifier having an HLB of at least 10 in theself-emulsifying composition of the present invention is notparticularly limited as long as it is at least 10 parts by weight inrelation to 100 parts by weight of the ω3PUFA. The content is typically10 to 100 parts by weight, preferably 10 to 80 parts by weight, and morepreferably 10 to 50 parts by weight in relation to 100 parts by weightof the ω3PUFA.

In the present invention, the “lecithin” is a type ofglycerophospholipid, and examples include soybean lecithin,enzymatically decomposed soybean lecithin, hydrogenated soybeanlecithin, egg yolk lecithin, hydrogenated phospholipid, phospholipidfrom milk, lysolecithin, phosphatidyl choline, and phosphatidyl serine.The preferred are soybean lecithin, enzymatically decomposed soybeanlecithin, hydrogenated soybean lecithin, and egg yolk lecithin, and themore preferred are soybean lecithin. These may be used alone or incombination of two or more. In the present invention, the “lecithin”includes all of such compounds unless otherwise noted.

Commercially available products include purified soybean lecithin(Nisshin Oilio), purified egg yolk lecithin (Asahi Kasei PharmaCorporation), and egg yolk lecithin PL-100M (Kewpie Corporation), anduse of such product is also possible.

In the present invention, the “polyhydric alcohol” is a polyol compoundhaving the structure of a straight chain or cyclic aliphatic hydrocarbonwherein two or more carbon atoms are each substituted with one hydroxygroup. Exemplary such polyhydric alcohols include divalent alcohols suchas ethyleneglycol, propylene glycol, trimethylene glycol, 1,2-butyleneglycol, tetramethylene glycol, 1,3-butylene glycol, 2,3-butylene glycol,and pentamethylene glycol; trivalent alcohols such as glycerin,trimethylolpropane, and 1,2,6-hexane triol, and polyhydric alcoholpolymers such as diethylene glycol, dipropylene glycol, triethyleneglycol, polyethylene glycol, polypropylene glycol, and polyglycerin, andthe preferred are propylene glycol or glycerin. In the presentinvention, the “polyhydric alcohol” includes all of such compoundsunless otherwise noted.

Total amount of the lecithin and the polyhydric alcohol added in theself-emulsifying composition of the present inventionis not particularlylimited. However, the total amount of the lecithin and the polyhydricalcohol is typically 0 to 50 parts by weight, preferably 3 to 40 partsby weight, and more preferably 5 to 30 parts by weight in relation to100 parts by weight of the ω3PUFA.

The ethanol in the self-emulsifying composition of the present inventionis preferably used at an amount not causing quality change in the courseof capsulation, distribution, or storage, at an amount not causingchange in the content of the capsule, and at an amount not exceeding theestablished upper limit of the daily dose as a drug. The ethanol contentis typically up to 10% by weight, preferably up to 4% by weight, morepreferably up to 1% by weight, more preferably up to 0.5% by weight,more preferably up to 0.2% by weight, still more preferably up to 0.1%by weight, and most preferably 0% by weight (no ethanol addition).

Preferable ethanol concentration can be adequately determined inconsideration of the ω3PUFA concentration in the self-emulsifyingcomposition and the daily dose. When the self-emulsifying composition ofthe present invention is orally administered at a daily dose in terms ofthe ω3PUFA of 1800 mg, and for example, the preparation contains 75% byweight of the ω3PUFA, the maximum daily dose of 3.26 mg described in“Dictionary of Drug Additives (in Japanese)” will not be exceeded whenthe ethanol content is not more than 0.135% by weight.

The preferable embodiment of the self-emulsifying composition of thepresent invention containing such ω3PUFA and an emulsifier is acombination of EPA-E and/or DHA-E with at least one emulsifier selectedfrom the group consisting of polyoxyethylene hydrogenated castor oil,polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil,sucrose fatty acid ester, and lecithin. When the self-emulsifyingcomposition of the present invention is used as a food such as specialpurpose food, functional health food, and health food, the preferred isthe combination of EPA-E and/or DHA-E with a sucrose fatty acid esterand/or a lecithin which has good results as a food additive. When asucrose fatty acid ester is used, the preferable amount is 1% by weightto 20% by weight, more preferably 4% by weight to 20% by weight, andmost preferably 4% by weight to 10% by weight in the self-emulsifyingcomposition. The most preferable embodiments are a combination of EPA-Eand polyoxyethylene (50) hydrogenated castor oil or polyoxyethylene (60)hydrogenated castor oil; a combination of EPA-E and polyoxyethylene (20)sorbitan monooleate; a combination of EPA-E and polyoxyethylene castoroil; and a combination of EPA-E and sucrose fatty acid ester J-1216 orJ-1816.

Also preferred is the further combination with a lecithin such assoybean lecithin and/or a polyhydric alcohol such as propylene glycol.

When the emulsifier is at least one member selected from the groupconsisting of polyoxyethylene hydrogenated castor oil, polyoxyethylenesorbitan fatty acid ester, and polyoxyethylene castor oil, thepolyhydric alcohol is preferably a dihydric alcohol, and use ofpropylene glycol is more preferable. When the emulsifier is a sucrosefatty acid ester, the polyhydric alcohol is preferably a trihydricalcohol, and use of glycerin is more preferable.

Preferably, the composition and therapeutic agent of the presentinvention is substantially free from water. The “substantially free fromwater” means that the water content is up to 10% by weight, preferablyup to 5% by weight, and even more preferably up to 3% by weight.

The dose and dosage period of the ω3PUFA used in the self-emulsifyingcomposition of the present invention is a dose and period sufficient forrealizing the intended action, which may be adequately adjusteddepending on the administration route, frequency of administration perday, seriousness of the symptoms, body weight, age, and other factors.

In the case of oral administration, the composition may be administeredat a dose in terms of the EPA-E of 0.1 to 5 g/day, preferably 0.2 to 3g/day, more preferably 0.4 to 1.8 g/day, and most preferably 0.6 to 0.9g/day in 1 to 3 divided doses. However, the entire dose may beadministered at once or in several divided doses. While meal affectsabsorption of the EPA-E, and the administration of the EPA-E ispreferably conducted during the meal or after the meal, and morepreferably immediately after the meal (within 30 minutes after themeal), the self-emulsifying composition of the present invention hasexcellent absorption under fasting, and therefore, it exhibits theintended effects even when administered at a timing other than during,after, or immediately after the meal, for example, before or immediatelybefore the meal or before going to the bed; to patients with reducedabsorption ability of the intestinal tract (for example, elderly,patients of intestinal disease, patients after intestinal surgery,terminal cancer patients, or patients taking a lipase inhibitor); orused at a reduced dose.

When orally administered at such dose, the administration period may beadequately determined depending on the target disease and degree ofsymptoms. For example, in the case of administration to dyslipidemia,the administration period is not particularly limited as long asimprovements of biochemical markers related to dyslipidemia, improvementin the pathological conditions or therapeutic effects, and suppressionof the progress in metabolic syndrome, cardio- or cerebrovascular event,or ulcer and gangrene of extremities and peripheries are realized.However, administration period is determined to realize the improvementsin the concentration of plasma lipid marker (total cholesterol(hereinafter abbreviated as Cho), TG, postprandial TG, low-densitylipoprotein Cho, high-density lipoprotein Cho, very-low-densitylipoprotein Cho, non-high-density lipoprotein Cho, intermediate-densitylipoprotein Cho, very-high-density lipoprotein Cho, free fatty acid,phospholipid, chylomicron, ApoB, lipoprotein(a), remnant-likelipoprotein Cho, small dense low-density lipoprotein Cho, etc.),increase in the skin temperature of extremities and peripheries whichcan be measured by thermography or the like, increase in the walkingdistance, increase in the serum CPK or other test value, and improvementof various symptoms such as numbness, coldness, ache, pain at rest,itching, cyanosis, flare, chilblain, neck stiffness, anemia, poorcomplexion, itching, and crawling. The amelioration or therapeuticeffects may be monitored by other biochemical, pathlogical, orsymptomatic parameters related to dyslipidemia or peripheral disruptionof blood circulation. The administration is preferably continued as longas abnormality is observed in biochemical index such as serum lipidconcentration or pathology. In addition, the composition may beadministered every alternate day or 2 or 3 days in a week, or as thecase may be, a drug withdrawal period of about 1 day to 3 month, andmore preferably about 1 week to 1 month may be included.

If indicated by the physician, oral administration may be started at adose lower than the recommended daily ω3PUFA dose at the first day, andthen, the dose may be gradually increased to the maximum daily dose asthe maintenance dose. The dose may be reduced depending on theconditions of the patient. Lower daily dose is preferable in view ofreducing the side effects, and administration of once or twice a day ispreferable in view of the drug compliance.

The self-emulsifying composition of the present invention may alsocontain additives such as an emulsion aid, stabilizer, antiseptic,surfactant, and antioxidant. Exemplary emulsion aids include fatty acidscontaining 12 to 22 carbon atoms such as stearic acid, oleic acid,linoleic acid, palmitic acid, linolenic acid, and myristic acid andtheir salts. Exemplary stabilizers include phosphatidic acid, ascorbicacid, glycerin, and cetanols, and exemplary antiseptics include ethylparaoxybenzoate and propyl paraoxybenzoate. Exemplary surfactantsinclude sucrose fatty acid esters, sorbitan fatty acid esters, glycerinfatty acid esters, polyglycerin fatty acid esters, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene alkyl ethers,polyoxyethylene fatty acid esters, polyoxyethylene alkyl phenyl ethers,and polyoxyethylene polyoxypropylene alkyl ethers having an HLB of lessthan 10. Exemplary antioxidants include oil-soluble antioxidants such asbutylated hydroxy toluene, butylated hydroxy anisole, propyl gallate,propyl gallate, pharmaceutically acceptable quinone, astaxanthin, andα-tocopherol.

In addition, an adequate carrier or mediater, a colorant, a flavor, andoptionally, a vegetable oil or an additive such as non-toxic organicsolvent or non-toxic solubilizing agent (for example glycerin),emulsifier, suspending agent (for example, Tween 80 and gum arabicsolution), isotonic agent, pH adjusting agent, stabilizer, corrective,flavoring agent, preservative, antioxidant, or absorption promotercommonly used in the art may be adequately combined to prepare anappropriate pharmaceutical preparation.

More specifically, since the ω3PUFA is highly unsaturated, effectiveamount of an oil-soluble antioxidant, for example, at least one memberselected from butylated hydroxytoluene, butylated hydroxyanisole, propylgallate, propyl gallate, pharmaceutically acceptable quinone,astaxanthin, and α-tocopherol is preferably incorporated in thecomposition. Storage temperature is preferably room temperature, andfrozen storage is preferably avoided since the freezing may result inthe loss of self-emulsifying property, dispersibility in thecomposition, or emulsion stability.

The self-emulsifying composition of the present invention may beadministered to the patient orally, endrectally, or transvaginally.However, oral administration is preferable in the case of the patientwho can take the drug orally, and the composition may be administered inthe form of a jelly preparation in the case of patients undergoingdialysis or patients with aphagia by jelling the composition withgelatin or the like.

The self-emulsifying composition of the present invention can beproduced by mixing the ω3PUFA, the emulsifier having an HLB of at least10, and the optionally added components such as lecithin, polyhydricalcohol, and antioxidant with optional heating to dissolve thecomponents.

The self-emulsifying composition of the present invention may be used bycombining with a second effective component. The second effectivecomponent may be adequately determined depending on the target diseaseand the seriousness of the symptom. However, the second effectivecomponent is preferably a component that does not adversely affect theeffects of the ω3PUFA, and examples include therapeutic agent forhyperlipidemia, antihypertensives, antidiabetics, antioxidants, bloodflow improving agents, and bile acid derivatives.

Of the preferable examples of the second effective component, exemplarytherapeutic agents for hyperlipidemia includepolyenephosphatidylcholine, unsaponifiable soybean oil (soy sterol),gamma-oryzanol, riboflavin butyrate, dextran sulfate sodium sulfur 18,pantethine, and elastase; statins such as pravastatin, simvastatin,atorvastatin, fluvastatin, pitavastatin, rosuvastatin, and cerivastatin;fibrates such as simfibrate, clofibrate, clinofibrate, bezafibrate, andfenofibrate; lipolytic enzyme inhibitors such as orlistat andcetilistat; resins such as colestyramine and colestimide; and ezetimibe.

Exemplary antihypertensives include angiotensin II receptor blockerssuch as irbesartan, olmesartan medoxomil, candesartan cilexetil,telmisartan, valsartan, and losartan potassium; angiotensin-convertingenzyme inhibitors such as alacepril, imidapril hydrochloride, enalaprilmaleate, captopril, quinapril hydrochloride, cilazapril hydrate,temocapril hydrochloride, delapril hydrochloride, trandolapril,benazepril hydrochloride, perindopril, and lisinopril hydrate; calciumantagonists such as azelnidipine, amlodipine besylate, aranidipine,efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride,nifedipine, nimodipine, nitrendipine, nilvadipine, barnidipinehydrochloride, felodipine, benidipine, and manidipine; a receptorblocker such as tolazoline, and phentolamine; β receptor blockers suchas atenolol, metoprolol, acebutolol, propranolol, pindolol, carvedilol,and labetalol hydrochloride; a receptors stimulant such as clonidine andmethyldopa; and diuretics such as eplerenone, hydrochlorothiazide, andfurosemide.

Exemplary antidiabetics include α-glucosidase inhibitors such asacarbose, voglibose, and miglitol; sulfonyl urea hypoglycemics such asgliclazide, glibenclamide, glimepiride, and tolbutamide; fast-actinginsulin secretagogues such as nateglinide and mitiglinide; biguanidehypoglycemics such as metformin hydrochloride and buforminhydrochloride; dipeptidyl phosphatase 4 inhibitors such as sitagliptin,vildagliptin, alogliptin, and saxagliptin; thiazolidine reagents such aspioglitazone hydrochloride and rosiglitazone maleate; and glucagon-likepeptide 1 derivative reagents such as exenatide and liraglutide.

Exemplary antioxidants include vitamins such as ascorbic acid (vitaminC), tocopherol (vitamin E), and tocopherol nicotinate, andN-acetylcysteine, probucol.

Exemplary blood flow improving agents include cilostazol, ticlopidinehydrochloride, alprostadil, limaprost, beraprost sodium, sarpogrelatehydrochloride, argatroban, naftidrofuryl, isoxsuprine hydrochloride,batroxobin, dihydroergotoxine mesilate, tolazoline hydrochloride,hepronicate, and shimotsu-to extract.

Exemplary bile acid derivatives include ursodeoxycholic acid,chenodeoxycholic acid, bile powder, deoxycholic acid, cholic acid, bileextract, bear bile, oriental bezoar, and dehydrocholic acid. Preferableexamples also include biotin (vitamin B7), cyanocobalamin (vitamin B12),pantothenic acid (vitamin B5), folic acid (vitamin B9), thiamine(vitamin B1), vitamin A, vitamin D, vitamin K, tyrosine, pyridoxine(vitamin B6), branched chain amino acids such as leucine, isoleucine,and valine, calcium, iron, zinc, copper, and magnesium. Other examplesinclude components used in designated health foods and functionalnutritional foods such as soy protein, chitosan, low molecular weightsodium alginate, dietary fiber from psyllium seed coat, soy peptide withbound phospholipids, phytosterol ester, plant stanol ester,diacylglycerol, globin digest, and tea catechin.

The self-emulsifying composition of the present invention may preferablyhave at least one of the effects including excellent self-emulsifyingproperty, excellent dispersibility in the composition, excellentemulsion stability, excellent storage stability, excellent absorptionproperty, and in particular, excellent absorption property and rateunder fasting, and excellent convenience or compliance for the patientsso that the composition can exhibit pharmacological effect of theω3PUFA.

The self-emulsifying composition of the present invention can be used asa therapeutic agent for various diseases of animals, and in particular,mammals, for example, therapeutic agent for dyslipidemia, therapeuticagent for postprandial hypertriglyceridemia, anti-arteriosclerosisagent, platelet aggregation suppressant, therapeutic agent forperipheral circulatory insufficiency, therapeutic agent for inflammatorydiseases, anticancer agent, and therapeutic agent for central disease.The self-emulsifying composition of the present invention isparticularly effective for amelioration, treatment, or secondaryprevention of dyslipidemia and postprandial hypertriglyceridemia, orprevention of the progress of the metabolic syndrome, cardio- orcerebrovascular event, or ulcer and gangrene of extremities andperipherie. Exemplary mammals include human, domestic animals such ascow, horse, and pig, and companion animals such as dog, cat, rabbit,rat, and mouse, and the preferred is human. The self-emulsifyingcomposition of the present invention is particularly expected to exhibitamelioration or therapeutic effects for dyslipidemia and postprandialhypertriglyceridemia in dyslipidemia patients such as metabolic syndromepatients experiencing increase in blood lipid, expression of insulinresistance, or increase in blood pressure. The self-emulsifyingcomposition of the present invention can reduce burden of the patientsby reducing the dose and daily frequency of the administration, andhence, by improving the drug compliance. This also results in the highereffects of amelioration or treatment.

EXAMPLES

Next, the present invention is described in further detail by referringto the following Examples which by no means limit the scope of theinvention.

Example 1

0.5 g of soybean lecithin, 1.0 g of polyoxyethylene (60) hydrogenatedcastor oil, 0.4 g of propylene glycol, and 3.1 g of EPA-E were weighed,and mixed while heating to a temperature of about 70° C. to prepare aself-emulsifying composition. After substituting with nitrogen, theself-emulsifying composition was hermetically sealed and stored at roomtemperature until the evaluation. Formulation of the self-emulsifyingcomposition is shown in Table 1.

TABLE 1 Ingredients Formulation (% by weight) EPA-E 62.0 Soybeanlecithin 10.0 Polyoxyethylene (60) hydrogenated castor oil 20.0Propylene glycol 8.0 Total 100.0

Example 2

0.5 g of soybean lecithin, 1.0 g of polyoxyethylene (50) hydrogenatedcastor oil, 0.4 g of propylene glycol, and 3.1 g of EPA-E were weighed,and a self-emulsifying composition was prepared and stored by repeatingthe procedure of Example 1. Formulation of the self-emulsifyingcomposition is shown in Table 2.

TABLE 2 Ingredients Formulation (% by weight) EPA-E 62.0 Soybeanlecithin 10.0 Polyoxyethylene (50) hydrogenated castor oil 20.0Propylene glycol 8.0 Total 100.0

Example 3

0.5 g of soybean lecithin, 0.9 g of polyoxyethylene castor oil, 0.6 g ofpropylene glycol, and 3.0 g of EPA-E were weighed, and aself-emulsifying composition was prepared and stored by repeating theprocedure of Example 1. Formulation of the self-emulsifying compositionis shown in Table 3.

TABLE 3 Ingredients Formulation (% by weight) EPA-E 60.0 Soybeanlecithin 10.0 Polyoxyethylene castor oil 18.0 Propylene glycol 12.0Total 100.0

Example 4

0.6 g of soybean lecithin, 0.6 g of polyoxyethylene (60) hydrogenatedcastor oil, 0.5 g of propylene glycol, and 3.3 g of EPA-E were weighed,and a self-emulsifying composition was prepared and stored by repeatingthe procedure of Example 1. Formulation of the self-emulsifyingcomposition is shown in Table 4.

TABLE 4 Ingredients Formulation (% by weight) EPA-E 66.0 Soybeanlecithin 12.0 Polyoxyethylene (60) hydrogenated castor oil 12.0Propylene glycol 10.0 Total 100.0

Example 5

0.5 g of soybean lecithin, 0.5 g of polyoxyethylene (50) hydrogenatedcastor oil, 0.5 g of propylene glycol, and 3.5 g of EPA-E were weighed,and a self-emulsifying composition was prepared and stored by repeatingthe procedure of Example 1. Formulation of the self-emulsifyingcomposition is shown in Table 5.

TABLE 5 Ingredients Formulation (% by weight) EPA-E 70.0 Soybeanlecithin 10.0 Polyoxyethylene (50) hydrogenated castor oil 10.0Propylene glycol 10.0 Total 100.0

Example 6

0.3 g of soybean lecithin, 0.3 g of polyoxyethylene (20) sorbitanmonooleate, 0.9 g of polyoxyethylene (60) hydrogenated castor oil, 0.4 gof propylene glycol, and 3.1 g of EPA-E were weighed, and aself-emulsifying composition was prepared and stored by repeating theprocedure of Example 1. Formulation of the self-emulsifying compositionis shown in Table 6.

TABLE 6 Ingredients Formulation (% by weight) EPA-E 62.0 Soybeanlecithin 6.0 Polyoxyethylene (20) sorbitan monooleate 6.0Polyoxyethylene (60) hydrogenated castor oil 18.0 Propylene glycol 8.0Total 100.0

Example 7

2.0 g of polyoxyethylene (20) sorbitan monooleate, 0.35 g of sorbitansesquioleate, and 2.65 g of EPA-E were weighed, and a self-emulsifyingcomposition was prepared and stored by repeating the procedure ofExample 1. Formulation of the self-emulsifying composition is shown inTable 7.

TABLE 7 Ingredients Formulation (% by weight) EPA-E 53.0 Polyoxyethylene(20) sorbitan monooleate 40.0 Sorbitan sesquioleate 7.0 Total 100.0

Example 8

0.5 g of soybean lecithin, 0.9 g of polyoxyethylene (40) hydrogenatedcastor oil, 0.6 g of propylene glycol, and 3.0 g of EPA-E were weighed,and a self-emulsifying composition was prepared and stored by repeatingthe procedure of Example 1. Formulation of the self-emulsifyingcomposition is shown in Table 8.

TABLE 8 Ingredients Formulation (% by weight) EPA-E 60.0 Soybeanlecithin 10.0 Polyoxyethylene (40) hydrogenated castor oil 18.0Propylene glycol 12.0 Total 100.0

Example 9

27.0 g of soybean lecithin, 21.0 g of polyoxyethylene (20) sorbitanmonooleate, 30.0 g of polyoxyethylene castor oil, 27.0 g of propyleneglycol, and 195.0 g of EPA-E were weighed, and a self-emulsifyingcomposition was prepared and stored by repeating the procedure ofExample 1. Formulation of the self-emulsifying composition is shown inTable 9.

TABLE 9 Ingredients Formulation (% by weight) EPA-E 65.0 Soybeanlecithin 9.0 Polyoxyethylene (20) sorbitan monooleate 7.0Polyoxyethylene castor oil 10.0 Propylene glycol 9.0 Total 100.0

Example 10

1.2 g of enzymatically decomposed soybean lecithin, 1.2 g of Surfhope SEPHARMA J-1216 (Mitsubishi-Kagaku Foods Corporation), and 5.1 g ofconcentrated glycerin were weighed, and mixed until the mixture becamehomogeneous with heating to a temperature of about 80° C. Next, 22.5 gof EPA-E was gradually added to the mixture with stirring to prepare aself-emulsifying composition. After substituting with nitrogen, theself-emulsifying composition was hermetically sealed and stored at roomtemperature until the evaluation. Formulation of the self-emulsifyingcomposition is shown in Table 10.

TABLE 10 Ingredients Formulation (% by weight) EPA-E 75.0 Enzymaticallydecomposed soybean lecithin 4.0 Surfhope SE PHARMA J-1216 4.0Concentrated glycerin 17.0 Total 100.0

Example 11

24.0 g of Surfhope SE PHARMA J-1216 and 51.0 g of concentrated glycerinwere weighed, and mixed until the mixture became homogeneous withheating to a temperature of about 80° C. Next, 225.0 g of EPA-E wasgradually added to the mixture with stirring to prepare aself-emulsifying composition. After substituting with nitrogen, theself-emulsifying composition was hermetically sealed and stored at roomtemperature until the evaluation. Formulation of the self-emulsifyingcomposition is shown in Table 11.

TABLE 11 Ingredients Formulation (% by weight) EPA-E 75.0 Surfhope SEPHARMA J-1216 8.0 Concentrated glycerin 17.0 Total 100.0

Example 12

24.0 g of Surfhope SE PHARMA J-1816 (Mitsubishi-Kagaku FoodsCorporation) and 51.0 g of concentrated glycerin were weighed, and mixeduntil the mixture became homogeneous with heating to a temperature ofabout 80° C. A self-emulsifying composition was prepared and stored asin the case of Example 11. Formulation of the self-emulsifyingcomposition is shown in Table 12.

TABLE 12 Ingredients Formulation (% by weight) EPA-E 75.0 Surfhope SEPHARMA J-1816 8.0 Concentrated glycerin 17.0 Total 100.0

Example 13

15.0 g of soybean lecithin, 21.0 g of Surfhope SE PHARMA J-1216, and39.0 g of concentrated glycerin were weighed, and mixed until themixture became homogeneous with heating to a temperature of about 80° C.A self-emulsifying composition was prepared and stored as in the case ofExample 11. Formulation of the self-emulsifying composition is shown inTable 13.

TABLE 13 Ingredients Formulation (% by weight) EPA-E 75.0 Soybeanlecithin 5.0 Surfhope SE PHARMA J-1216 7.0 Concentrated glycerin 13.0Total 100.0

Comparative Example 1

1.5 g of soybean lecithin, 0.4 g of propylene glycol, and 3.1 g of EPA-Ewere weighed, and a composition was prepared and stored by repeating theprocedure of Example 1. Formulation of the composition is shown in Table14.

TABLE 14 Ingredients Formulation (% by weight) EPA-E 6.0 Soybeanlecithin 30.0 Propylene glycol 8.0 Total 100.0

Comparative Example 2

0.13 g of soybean lecithin, 0.3 g of polyoxyethylene (20) sorbitanmonooleate, 0.22 g of absolute ethanol, and 4.35 g of EPA-E wereweighed, and a composition was prepared. After substituting withnitrogen, the composition was hermetically sealed and stored at roomtemperature until the evaluation. Formulation of the composition isshown in Table 15.

TABLE 15 Ingredients Formulation (% by weight) EPA-E 87.0 Soybeanlecithin 2.0 Polyoxyethylene (20) sorbitan monooleate 6.0 Absoluteethanol 4.0 Total 100.0

Experimental Example 1 Evaluation of Self-Emulsifying Property

The self-emulsifying compositions of the Examples 1 to 8 and 10 to 13and the compositions of Comparative Example 1 and 2 were evaluated fortheir self-emulsifying property by dropping 0.05 g of each compositionto 7 ml of purified water at 37° C. in test tube. The result wasevaluated “good” when the composition emulsified merely by dropping, and“fail” when the composition failed to undergo natural emulsificationmerely by the dropping. Next, the mixture was lightly stirred under thesame conditions for all compositions to evaluate their conditions. Thedispersibility of the composition was evaluated “good” when thecomposition was dispersed, and “fail” when a part of the compositionremained non-dispersed as a mass. The emulsion stability was evaluated“good” when separation of the oil content was not observed, and “fail”when such separation of the oil content was observed. In the case ofComparative Example 1, the emulsion stability was not evaluated sincethe composition was not emulsified. Table 16 shows the results of theevaluation.

TABLE 16 Self-emulsifying Dispersibility of Emulsion property thecomposition stability Example 1 good good good Example 2 good good goodExample 3 good good good Example 4 good good good Example 5 good goodgood Example 6 good good good Example 7 good good good Example 8 goodgood good Example 10 good good good Example 11 good good good Example 12good good good Example 13 good good good Comparative fail fail notdetermined Example 1 Comparative good good fail Example 2

In the case of the self-emulsifying composition of the Examples Ito 8and 10 to 13, the results were favorable for all of the self-emulsifyingproperty, the dispersibility of the composition, and the emulsionstability. The composition of Comparative Example 1 was not emulsified,and the composition of Comparative Example 2 was insufficient inemulsion stability while it exhibited good self-emulsifying property anddispersibility. The result that the self-emulsifying composition of thepresent invention could be used as a self-emulsifying preparation withgood emulsion stability indicates improvement of the absorption in thecase of the oral administration. In addition, the compositions of theExamples 1 to 13 are expected to be usable as praparations free from theproblems caused by the ethanol inclusion since ethanol is not used inthese compositions.

Experimental Example 2 Pharmacokinetics in Beagle

The compositions of the Examples 6, 7, 9, 10, 13, and ComparativeExample 2 were orally administered to 3 to 8 male beagles (34 to 45months old having a body weight of 11 to 17 kg, Kitayama Labes Co.,Ltd.) under fasting, and time course blood EPA concentration wasevaluated. The test animals were fasted at least for 18 hours before thetest, and each animal was administered with the composition at an amountof 600 mg in terms of the EPA-E. The blood was collected before theadministration and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24 hours after theadministration, and after separating and treating the plasma, plasma EPAconcentration was measured by LC/MS/MS. The EPA-E stock solution filledin a capsule was also administered to the control group animals. Table17 shows maximum blood concentration (Cmax), area under the curve of theblood concentration from 0 hour to 2 hours (AUC₀₋₂), and area under thecurve of the blood concentration from 0 hour to 24 hours (AUC₀₋₂₄)calculated from the test results. In calculating each parameter, thevalue was corrected by subtracting the blood EPA concentration beforethe administration from the blood concentration after theadministration.

TABLE 17 Cmax AUC₀₋₂ AUC₀₋₂₄ (μg/mL) (μg/mL · hr) (μg/mL · hr) Example 673.7 90.8 522.8 Example 7 78.8 84.7 559.0 Example 9 64.7 63.7 542.4Example 10 82.6 79.5 496.5 Example 13 67.5 54.3 471.6 ComparativeExample 2 26.8 21.0 358. EPA-E stock solution 16.6 14.4 188.0 (control)

The animals administered with the self-emulsifying compositions of theExamples 6, 7, 9, 10, and 13 exhibited the values of Cmax and AUC₀₋₂which are the parameter of absorption rate higher than the animalsadministered with the control group or the Comparative Examples. Morespecifically, the AUC₀₋₂ which is a parameter indicating the increase ofblood concentration immediately after the administration was about 3.8to 6.3 times higher in the animals administered with the composition ofthe Examples compared to the animals of the control group, and about 2.6to 4.3 times higher in the animals administered with the composition ofthe Examples compared to the animals administered with the compositionof the Comparative Example 2. Similarly, the Cmax value was about 3.9 to5.0 times higher in the animals administered with the composition of theExamples compared to the animals of the control group, and about 2.4 to3.1 times higher in the animals administered with the composition of theComparative Example 2. In the meanwhile, the AUC₀₋₂₄ which is theparameter for the absorption amount was about 2.5 to 3.0 times higher inthe animals administered with the composition of the Examples comparedto the animals of the control group, and about 1.3 to 1.6 times higherin the animals administered with the composition of the ComparativeExample 2. As described above, in the animals administered with theself-emulsifying compositions of the Examples, not only the amount ofEPA absorbed in the 24 hours after the oral administration but also theabsorption immediately after the administration increased compared tothe animals of the control group and animals administered with thecomposition of the comparative Example. Accordingly, theself-emulsifying composition of the present invention is expected toserve a self-emulsifying preparation which realizes faster and largerincrease in blood EPA concentration, and hence, more rapid and effectivepharmacological action even when administered under fasting such asbefore the meal or before going to bed.

Experimental Example 3 Pharmacokinetics in Cynomolgus Monkey

The compositions of the Example 6 was orally administered to 6cynomolgus monkies (2 to 5 years having a body weight of 2.70 to 4.65kg, Hamri Co., Ltd.) under fasting, and time course blood EPAconcentration was evaluated. The test animals were fasted at least for12 hours before the test, and each animal was administered with theself-emulsifying composition at an amount of 4.5 mg/kg in terms of theEPA-E. The EPA-E stock solution filled in a capsule was alsoadministered to the control group animals. The blood was collectedbefore the administration and at 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72hours after the administration, and after separating and treating theplasma, plasma EPA was measured by LC/MS/MS. Table 18 shows maximumblood concentration (Cmax), area under the curve of the bloodconcentration from 0 hour to 12 hours (AUC₀₋₁₂), and area under thecurve of the blood concentration from 0 hour to 72 hours (AUC₀₋₇₂)calculated from the test results. In calculating each parameter, thevalue was corrected by subtracting the blood EPA concentration beforethe administration from the blood concentration after theadministration.

TABLE 18 Cmax AUC₀₋₁₂ AUC₀₋₇₂ (μg/mL) (μg/mL · hr) (μg/mL · hr) Example6 71.4 510.4 1688.8 EPA-E stock solution 7.4 46.5 284.5 (control)

The animals administered with the composition of the Example 6experienced increase in all of the blood concentration parameterscompared to the animals of the control group, and in the case of Cmaxand AUC₀₋₁₂, the values increased about 10 fold. More specifically,administration of the self-emulsifying composition of Example 6 wasconfirmed to result not only in the increase of the absorbed amount, butalso, in the immediate EPA absorption after the oral administration.Accordingly, the self-emulsifying composition of the present inventionis expected to serve a self-emulsifying preparation which realizesfaster and larger increase in the blood EPA concentration, and hence,more rapid and effective pharmacological action even when administeredunder fasting such as before the meal or before going to bed.

Experimental Example 4 Effectiveness in Fasted Glucose Tolerance ModelRat

Male Sprague Dawley rats (10 week old, Charles River Laboratories Japan,Inc.) are divided into 4 groups each comprising 10 animals with evenbody weight and serum TG value. Control group is administered with oliveoil, EPA-E group is administered with EPA-E stock solution, Examplegroup is administered with the self-emulsifying composition of Example6, and comparative group is administered with the composition ofComparative Example 2 by filling in the gelatin capsule and perorallyadministering the capsule to the animals, respectively. The test animalsare fasted at least 24 hours before the administration, and each animalis administered with the composition at an amount of 100 mg/kg in termsof the olive oil or the EPA-E. 30 minutes after the administration,glucose solution in physiological saline is orally administered at 2g/kg. Blood is periodically collected from tail vein, and plasma TGconcentration and free fatty acid concentration are measured by using acommercially available assay kit. Change from the value before theglucose loading is calculated for each parameter.

In the control group, plasma TG concentration increases after theglucose loading, and suppressive effect for this increase is notobserved in the group administered with the EPA-E. However, increase inthe plasma TG concentration and free fatty acid concentration after theglucose loading is suppressed in the Example group and the ComparativeExample group, and the suppression effect is superior in the Examplegroup compared to the Comparative Example group.

Accordingly, the self-emulsifying compositions of the present inventionis useful in improving or treating the postprandial hypertriglyceridemiaand postprandial hyper free fatty acidemia by the administration beforethe meal.

Preparation Example 1 Self Emulsifying Capsule Preparation

The self-emulsifying compositions produced in Examples 1 to 7 at anamount of 200 mg in terms of EPA-E are encapsulated in a soft gelatincapsule or a hard gelatin capsule to prepare a self-emulsifying capsule.Self emulsifying capsules are also prepared by encapsulating theself-emulsifying compositions produces in Examples 1 to 7 together witha tocopherol at a final concentration of 0.2% in the capsule.

Preparation Example 2 Self Emulsifying Capsule Preparation

The procedure of Examples 1 to 7 is repeated by replacing EPA-E withω3PUFA (Lovaza (registered trade mark) (K85EE) containing about 90% ofω3PUFA and about 84% of EPA-E+DHA-E, EPA-E:DHA-E=about 1.2:1) to prepareself-emulsifying compositions. These self-emulsifying compositions at anamount of 200 mg in terms of the ω3PUFA are encapsulated in a softgelatin capsule or a hard gelatin capsule to prepare a self-emulsifyingcapsule. Self emulsifying capsules are also prepared by encapsulatingthe self-emulsifying composition together with a tocopherol at a finalconcentration of 0.2% in the capsule.

Preparation Example 3 Blended Self-Emulsifying Capsule Preparation

The procedure of the Example 6 is repeated by further adding 1.0 g oftocopherol nicotinate and/or 0.4 g of ursodeoxycholic acid to thecomposition of the Example 6 to thereby produce a self-emulsifyingcomposition. The self-emulsifying composition at an amount of 200 mg interms of the EPA-E is encapsulated in a soft gelatin capsule or a hardgelatin capsule to prepare a self-emulsifying capsule.

Preparation Example 4 Self Emulsifying Capsule Preparation

A soft gelatin capsule is prepared by rotary method by filling thecapsule with 200 mg of the self-emulsifying composition of Example 9.The self-emulsifying capsule prepared by this method exhibit a shapesimilar to the soft gelatin capsule filled solely with the EPA-E, anddeformation of the capsule film is not recognized.

INDUSTRIAL APPLICABILITY

The self-emulsifying composition of the present invention is capable ofproviding a self-emulsifying composition which has at least one ofexcellent self-emulsifying property, dispersibility in the composition,emulsion stability, and absorption property, and in particular, oralabsorption property and rate under fasting even though the compositioncontains no ethanol or has a low ethanol concentration by adding anemulsifier having an HLB of at least 10 to at least one member selectedfrom ω3PUFA and homogenating the mixture. Also provided a drug of suchself-emulsifying composition, its production method, and a method forits use.

The self-emulsifying composition of the present invention which can bemore rapidly absorbed even in the case of oral administration underfasting compared to conventional compositions is expected to showpreventive and therapeutic effects of the ω3PUFA. More specifically, theself-emulsifying composition of the present invention shows itseffectiveness by the administration of 1 to 2 times a day at non-limitedtiming, namely, without the limitation of the administering three timesa day immediately after the meal, and this convenience for the patientsleads to the improved drug compliance, and hence, further improvement inthe effectiveness. In addition, the self-emulsifying composition of thepresent invention can be combined with a drug which is administered notby the administration immediately after the meal, and also, a drug whichis a combination with such drug may also be produced. Furthermore, theself-emulsifying composition of the present invention shows variousclinical merits such as suppression of the serum TG increase after themeal by administering the composition before the meal and prevention ofessential fatty acid deficiency associated with lipase inhibitoradministration by administration of the composition before going to thebed.

Compared to the conventional emulsion preparation, the self-emulsifyingcomposition of the present invention can be produced, delivered, andstored at reduced cost and with less trouble. In addition, theself-emulsifying composition of the present invention can be preparedwater-free with higher concentration of the effective components, andhence, at reduced preparation volume, and this enables administration ofthe composition to patients with water intake restriction. Furthermore,the self-emulsifying composition of the present invention can beencapsulated in a gelatin capsule and the like, and this is expected toimprove both drug convenience and drug compliance.

Due to the non-inclusion or reduced inclusion of the ethanol in theself-emulsifying composition of the present invention, this compositionhas reduced risk of capsule deformation and bubble entrapment by theethanol volatilization during the capsulation step, and in particular,during the drying step, and also, reduced risk of capsule deformationand crack generation by the ethanol volatilization during thedistribution and storage process. This composition also has reduced riskof the denaturing such as clouding and separation of the capsule contentby the ethanol volatilization. Furthermore, side effects of the ethanolis absent or reduced in alcohol (ethanol) intolerant patients, and it isexpected that the composition can be safely administered for a longperiod.

1. A self-emulsifying composition comprising: 50 to 95% by weight in total of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids and their pharmaceutically acceptable salts and esters; and 5 to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10, and wherein ethanol content is up to 4% by weight in relation to the total content of the compound and the emulsifier.
 2. A self-emulsifying composition according to claim 1, wherein the composition does not contain ethanol.
 3. A self-emulsifying composition according to claim 1, wherein the emulsifier is at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and lecithin.
 4. A self-emulsifying composition according to claim 1, wherein the emulsifier is at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, and sucrose fatty acid ester.
 5. A self-emulsifying composition according to claim 3, wherein the polyoxyethylene hydrogenated castor oil is at least one member selected from the group consisting of polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, and polyoxyethylene (100) hydrogenated castor oil.
 6. A self-emulsifying composition according to claim 3, wherein the polyoxyethylene sorbitan fatty acid ester is at least one member selected from the group consisting of polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, and polyoxyethylene sorbitan monolaurate.
 7. A self-emulsifying composition according to claim 3, wherein the sucrose fatty acid ester is at least one member selected from the group consisting of sucrose laurate, sucrose myristate, sucrose palmitate, sucrose stearate, and sucrose oleate.
 8. A self-emulsifying composition according to claim 1, wherein the composition contains a lecithin.
 9. A self-emulsifying composition according to claim 8, wherein the lecithin is at least one member selected from the group consisting of soybean lecithin, enzymatically decomposed soybean lecithin, hydrogenated soybean lecithin, and egg yolk lecithin.
 10. A self-emulsifying composition according to claim 1, wherein the composition contains a polyhydric alcohol.
 11. A self-emulsifying composition according to claim 10, wherein the polyhydric alcohol is propylene glycol or glycerin.
 12. A self-emulsifying composition according to claim 1, wherein the composition contains at least one member selected from the group consisting of eicosapentaenoic acid, docosahexaenoic acid, and their pharmaceutically acceptable salts and esters.
 13. A self-emulsifying composition according to claim 1, wherein the composition contains ethyl icosapentate and/or ethyl docosahexaenoate.
 14. A self-emulsifying composition according to claim 1, wherein total content of the emulsifier having an HLB of at least 10 is 10 to 100 parts by weight in relation to 100 parts by weight of the at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids and their pharmaceutically acceptable salts and esters.
 15. A self-emulsifying composition according to claim 1, wherein total content of the emulsifier having an HLB of at least 10 is 10 to 50 parts by weight in relation to 100 parts by weight of the at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids and their pharmaceutically acceptable salts and esters.
 16. A method for administering to a human under fasting or before sleeping with at least one compound selected from the group consisting of ω3PUFA and pharmaceutically acceptable salts and esters thereof, comprising the steps of: adding at least 10 parts by weight the emulsifier having an HLB of at least 10 to 100 parts by weight in total of the compound; stirring the mixture; and administering the mixture to human.
 17. A method for increasing plasma ω3PUFA concentration comprising the steps of: adding at least 10 parts by weight the emulsifier having an HLB of at least 10 to 100 parts by weight in total of at least one compound selected from the group consisting of ω3PUFA and pharmaceutically acceptable salts and esters thereof; stirring the mixture; and administering the mixture to human under fasting or before sleeping to thereby increase the plasma ω3PUFA concentration. 